Engineering anti-Lewis-Y hu3S193 antibodies with improved therapeutic ratio for radioimmunotherapy of epithelial cancers

Ingrid J.G. Burvenich, Fook-Thean Lee, Graeme J. O’Keefe, Dahna Makris, Diana X Cao, Sylvia Jie Gong, Angela Rigopoulos, Laura C. Allan, Martin W Brechbiel, Zhanqi Liu, Paul A. Ramsland, Andrew M. Scott

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Abstract

Background: The aim of the study was to explore Fc mutations of a humanised anti-Lewis-Y antibody (IgG1) hu3S193 as a strategy to improve therapeutic ratios for therapeutic payload delivery. Methods: Four hu3S193 variants (I253A, H310A, H435A and I253A/H310A) were generated via site-directed mutagenesis and radiolabelled with diagnostic isotopes iodine-125 or indium-111. Biodistribution studies in Lewis-Y-positive tumour-bearing mice were used to calculate the dose in tumours and organs for therapeutic isotopes (iodine-131, yttrium-90 and lutetium-177). Results: 111In-labelled I253A and H435A showed similar slow kinetics (t1/2β, 63.2 and 62.2 h, respectively) and a maximum tumour uptake of 33.11 ± 4.05 and 33.69 ± 3.77 percentage injected dose per gramme (%ID/g), respectively. 111In-labelled I253A/H310A cleared fastest (t1/2β, 9.1 h) with the lowest maximum tumour uptake (23.72 ± 0.85 %ID/g). The highest increase in tumour-to-blood area under the curve (AUC) ratio was observed with the metal-labelled mutants (90Y and 177Lu). 177Lu-CHX-A" DTPA-hu3S193 I253A/H310A (6:1) showed the highest tumour-to-blood AUC ratio compared to wild type (3:1) and other variants and doubling of calculated dose to tumour based on red marrow dose constraints. Conclusions: These results suggest that hu3S193 Fc can be engineered with improved therapeutic ratios for 90Y- and 177Lu-based therapy, with the best candidate being hu3S193 I253A/H310A for 177Lu-based therapy.

Original languageEnglish
Article number26
Number of pages13
JournalEJNMMI Research
Volume6
Issue number1
DOIs
Publication statusPublished - 1 Dec 2016

Keywords

  • Antibody engineering
  • Lewis-Y
  • Payload delivery
  • Small animal imaging
  • Therapeutic ratio

Cite this

Burvenich, Ingrid J.G. ; Lee, Fook-Thean ; O’Keefe, Graeme J. ; Makris, Dahna ; Cao, Diana X ; Gong, Sylvia Jie ; Rigopoulos, Angela ; Allan, Laura C. ; Brechbiel, Martin W ; Liu, Zhanqi ; Ramsland, Paul A. ; Scott, Andrew M. / Engineering anti-Lewis-Y hu3S193 antibodies with improved therapeutic ratio for radioimmunotherapy of epithelial cancers. In: EJNMMI Research. 2016 ; Vol. 6, No. 1.
@article{42a9edc13a824034b6afb205c605c859,
title = "Engineering anti-Lewis-Y hu3S193 antibodies with improved therapeutic ratio for radioimmunotherapy of epithelial cancers",
abstract = "Background: The aim of the study was to explore Fc mutations of a humanised anti-Lewis-Y antibody (IgG1) hu3S193 as a strategy to improve therapeutic ratios for therapeutic payload delivery. Methods: Four hu3S193 variants (I253A, H310A, H435A and I253A/H310A) were generated via site-directed mutagenesis and radiolabelled with diagnostic isotopes iodine-125 or indium-111. Biodistribution studies in Lewis-Y-positive tumour-bearing mice were used to calculate the dose in tumours and organs for therapeutic isotopes (iodine-131, yttrium-90 and lutetium-177). Results: 111In-labelled I253A and H435A showed similar slow kinetics (t1/2β, 63.2 and 62.2 h, respectively) and a maximum tumour uptake of 33.11 ± 4.05 and 33.69 ± 3.77 percentage injected dose per gramme ({\%}ID/g), respectively. 111In-labelled I253A/H310A cleared fastest (t1/2β, 9.1 h) with the lowest maximum tumour uptake (23.72 ± 0.85 {\%}ID/g). The highest increase in tumour-to-blood area under the curve (AUC) ratio was observed with the metal-labelled mutants (90Y and 177Lu). 177Lu-CHX-A{"} DTPA-hu3S193 I253A/H310A (6:1) showed the highest tumour-to-blood AUC ratio compared to wild type (3:1) and other variants and doubling of calculated dose to tumour based on red marrow dose constraints. Conclusions: These results suggest that hu3S193 Fc can be engineered with improved therapeutic ratios for 90Y- and 177Lu-based therapy, with the best candidate being hu3S193 I253A/H310A for 177Lu-based therapy.",
keywords = "Antibody engineering, Lewis-Y, Payload delivery, Small animal imaging, Therapeutic ratio",
author = "Burvenich, {Ingrid J.G.} and Fook-Thean Lee and O’Keefe, {Graeme J.} and Dahna Makris and Cao, {Diana X} and Gong, {Sylvia Jie} and Angela Rigopoulos and Allan, {Laura C.} and Brechbiel, {Martin W} and Zhanqi Liu and Ramsland, {Paul A.} and Scott, {Andrew M.}",
year = "2016",
month = "12",
day = "1",
doi = "10.1186/s13550-016-0180-0",
language = "English",
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journal = "EJNMMI Research",
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Burvenich, IJG, Lee, F-T, O’Keefe, GJ, Makris, D, Cao, DX, Gong, SJ, Rigopoulos, A, Allan, LC, Brechbiel, MW, Liu, Z, Ramsland, PA & Scott, AM 2016, 'Engineering anti-Lewis-Y hu3S193 antibodies with improved therapeutic ratio for radioimmunotherapy of epithelial cancers', EJNMMI Research, vol. 6, no. 1, 26. https://doi.org/10.1186/s13550-016-0180-0

Engineering anti-Lewis-Y hu3S193 antibodies with improved therapeutic ratio for radioimmunotherapy of epithelial cancers. / Burvenich, Ingrid J.G.; Lee, Fook-Thean; O’Keefe, Graeme J.; Makris, Dahna; Cao, Diana X; Gong, Sylvia Jie; Rigopoulos, Angela; Allan, Laura C.; Brechbiel, Martin W; Liu, Zhanqi; Ramsland, Paul A.; Scott, Andrew M.

In: EJNMMI Research, Vol. 6, No. 1, 26, 01.12.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Engineering anti-Lewis-Y hu3S193 antibodies with improved therapeutic ratio for radioimmunotherapy of epithelial cancers

AU - Burvenich, Ingrid J.G.

AU - Lee, Fook-Thean

AU - O’Keefe, Graeme J.

AU - Makris, Dahna

AU - Cao, Diana X

AU - Gong, Sylvia Jie

AU - Rigopoulos, Angela

AU - Allan, Laura C.

AU - Brechbiel, Martin W

AU - Liu, Zhanqi

AU - Ramsland, Paul A.

AU - Scott, Andrew M.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Background: The aim of the study was to explore Fc mutations of a humanised anti-Lewis-Y antibody (IgG1) hu3S193 as a strategy to improve therapeutic ratios for therapeutic payload delivery. Methods: Four hu3S193 variants (I253A, H310A, H435A and I253A/H310A) were generated via site-directed mutagenesis and radiolabelled with diagnostic isotopes iodine-125 or indium-111. Biodistribution studies in Lewis-Y-positive tumour-bearing mice were used to calculate the dose in tumours and organs for therapeutic isotopes (iodine-131, yttrium-90 and lutetium-177). Results: 111In-labelled I253A and H435A showed similar slow kinetics (t1/2β, 63.2 and 62.2 h, respectively) and a maximum tumour uptake of 33.11 ± 4.05 and 33.69 ± 3.77 percentage injected dose per gramme (%ID/g), respectively. 111In-labelled I253A/H310A cleared fastest (t1/2β, 9.1 h) with the lowest maximum tumour uptake (23.72 ± 0.85 %ID/g). The highest increase in tumour-to-blood area under the curve (AUC) ratio was observed with the metal-labelled mutants (90Y and 177Lu). 177Lu-CHX-A" DTPA-hu3S193 I253A/H310A (6:1) showed the highest tumour-to-blood AUC ratio compared to wild type (3:1) and other variants and doubling of calculated dose to tumour based on red marrow dose constraints. Conclusions: These results suggest that hu3S193 Fc can be engineered with improved therapeutic ratios for 90Y- and 177Lu-based therapy, with the best candidate being hu3S193 I253A/H310A for 177Lu-based therapy.

AB - Background: The aim of the study was to explore Fc mutations of a humanised anti-Lewis-Y antibody (IgG1) hu3S193 as a strategy to improve therapeutic ratios for therapeutic payload delivery. Methods: Four hu3S193 variants (I253A, H310A, H435A and I253A/H310A) were generated via site-directed mutagenesis and radiolabelled with diagnostic isotopes iodine-125 or indium-111. Biodistribution studies in Lewis-Y-positive tumour-bearing mice were used to calculate the dose in tumours and organs for therapeutic isotopes (iodine-131, yttrium-90 and lutetium-177). Results: 111In-labelled I253A and H435A showed similar slow kinetics (t1/2β, 63.2 and 62.2 h, respectively) and a maximum tumour uptake of 33.11 ± 4.05 and 33.69 ± 3.77 percentage injected dose per gramme (%ID/g), respectively. 111In-labelled I253A/H310A cleared fastest (t1/2β, 9.1 h) with the lowest maximum tumour uptake (23.72 ± 0.85 %ID/g). The highest increase in tumour-to-blood area under the curve (AUC) ratio was observed with the metal-labelled mutants (90Y and 177Lu). 177Lu-CHX-A" DTPA-hu3S193 I253A/H310A (6:1) showed the highest tumour-to-blood AUC ratio compared to wild type (3:1) and other variants and doubling of calculated dose to tumour based on red marrow dose constraints. Conclusions: These results suggest that hu3S193 Fc can be engineered with improved therapeutic ratios for 90Y- and 177Lu-based therapy, with the best candidate being hu3S193 I253A/H310A for 177Lu-based therapy.

KW - Antibody engineering

KW - Lewis-Y

KW - Payload delivery

KW - Small animal imaging

KW - Therapeutic ratio

UR - http://www.scopus.com/inward/record.url?scp=84961674939&partnerID=8YFLogxK

U2 - 10.1186/s13550-016-0180-0

DO - 10.1186/s13550-016-0180-0

M3 - Article

VL - 6

JO - EJNMMI Research

JF - EJNMMI Research

SN - 2191-219X

IS - 1

M1 - 26

ER -